This project is designed to investigate the trafficking of CD8+ T-lymphocytes to the pulmonary microcirculation (alveolar capillaries) and the associated interstitial tissue/airways of the normal (noninflamed) murine lungs. Our long-term objective is to understand, in molecular terms, the factors which regulate activated CD8+ T-cell migration to the pulmonary microcirculation, the retention of those cells at the site, and the subsequent egress of the cells from the vascular compartment into the lung interstitium. It is based on our emerging evidence suggesting that activated CD8+ T-cells are retained in the normal lung environment, because they constitutively egress from the pulmonary circulation vascular compartment (i.e., alveolar capillaries) into the interstitium of the normal/non-inflamed lungs. Our data further suggests that prolonged T-cell retention and egress into the lung interstitium may be mediated by specific adhesive receptor/ligand interactions, and may be dependent on a chemokine-dependent homing/retention mechanism. To further explore this process of activated CD8+ T-cell homing/retention in the normal lungs, we propose the following Specific Aims: 1. To characterize the trafficking of naive (resting) and activated CD8+ T lymphocytes to the normal (non-inflamed) pulmonary microcirculation, and the egress of these cells into the alveolar interstitium; 2. To analyze the mechanism by which activated CD8+ T-cells home to the pulmonary micro capillary bed and egress into the interstitium of the normal lung. We will employ a variety of strategies including cell and whole animal imaging techniques to examine the retention and compartmentalization of transferred CD8+ T-cells within the normal lungs. The proposed analysis should provide new information on the factors controlling the interaction of T-lymphocytes with the pulmonary microcirculation and the associated interstitium/airways, as well as, on the underlying mechanism controlling this process.